Progressive Supranuclear Palsy (PSP) belongs to a family of neurodegenerative disorders referred to as tauopathies, and is the most frequent atypical neurodegenerative parkinsonian disorder, with an estimated prevalence of 4-6.5/ 100,000 in the general population. Symptoms of the disease usually appear between 50- 80 years of age, and include postural instability, supranuclear vertical gaze palsy, severe speech and swallowing difficulties, and alterations in mood and behavior. The disease is progressively debilitating and patients die within a few years after the onset of symptoms. To date there is no cure for PSP, and development of therapies for the disease require further understanding of the mechanisms underlying the neuropathological changes associated with PSP. A mouse model recapitulating the phenotypic features of the disease would therefore be an invaluable tool to understand the disease process and test new therapeutic strategies. Such mouse model has not been established yet. The main goal of this application is to generate a mouse model for PSP. The availability of a mouse model for PSP will allow not only further understanding of neuropathological changes that occur in tauopathies, but also the possibility of developing new therapeutic interventions for this devastating disorder. PUBLIC HEALTH RELEVANCE: Progressive Supranuclear Palsy (PSP) belongs to a family of neurodegenerative disorders called tauopathies and is the most frequent atypical neurodegenerative Parkinsonian disorder. The disease is inevitably fatal with death occurring a few years after symptoms appear. Generation and analyses of a mouse model for this disorder will provide insights for potential new therapeutic interventions for PSP and for other tauopathies.